The present invention relates to prostaglandin derivatives having cell membrane permeability and a process for preparation thereof.
As is well known, "prostaglandin" (PG) is a generic name of compounds that possess a common skeleton of prostanoic acid of the following formula. They are classified into the groups A, B, C, D, E, F, G/H and I, based on the position of double bond, presence and position of ketone, hydroxy, peroxide and condensed furan ring at the 5-membered ring thereof, and into the groups 1, 2, and 3 based on the number, position and stereochemistry of the double bond in the side chain. They include, for example, PGA.sub.1, PGA.sub.2, PGB.sub.1, PGB.sub.2, PGC.sub.2, PGD.sub.2, PGE.sub.1, PGE.sub.2, PGE.sub.3, PGF.sub.1 .alpha., PGF.sub.2 .alpha., PGF.sub.3 .alpha., PGG.sub.2, PGH.sub.2, PGI.sub.2, etc. ##STR1##
Prostaglandins exhibit a wide range of physiological activities such as hypotensive activity, diuretic activity, metabolic activity, bronchiectasic activity, uterotonic activity, thyrotropic activity, neuro stimulating activity, gastric juice secretion inhibiting activity, fatty acid release inhibiting activity, etc. Furthermore, in recent years, their carcinostatic activity has attracted special interest. Thus, their uses in pharmaceutical field have been more enhanced.
Since prostaglandins have no substantial permeability to cell membranes and in fact they are usually present outside the cell where they presumably exhibit various pharmacological activities in its original state, no attempt has been made to provide prostaglandins with special permeability to cell membranes.
In the course of the study on the physicochemical and physiological properties of the prostaglandins, it has been surprisingly discovered that when a cell membrane permeable substance having a hydroxy group or an amino group is introduced into carboxy group at 1-position through the intermediation of an ester bond to said hydroxy group or an amide bond to said amino group, the resulting prostaglandin esters or amides show an excellent cell membrane permeability. Although esterification (to methyl ester) and amidation (to dimethylamide) of carboxy group at 1-position of prostaglandin are known, no improvement on cell membrane permeability has been reported with respect to these derivatives. In spite of the fact that the cell membrane permeable substances used in the present invention have a greater bulk than methyl group, it was found that they could impart remarkably improved cell membrane permeability to the prostaglandins when they were combined with prostaglandins through an ester bond or an amide bond as aforedescribed. The prostaglandin esters and amides thus furnished with cell membrane permeability have a greater value than the parent compound because, in addition to the original physiological activity of prostaglandins as such, they show an ability of rapidly exhibiting such physiological activity.